Reaction Biology Corporation has developed an extremely low cost nanoliter reaction microarrays to serve markets for ultra high throughput screening (uHTS) drug discovery, large scale IC50 determinations, and large scale IC50 selectivity/toxicity profiling. These reactions are 1000 to 10,000-fold smaller than well plate formats used widely in drug discovery. Currently, 3072 drug screening reactions can be carried out on a single microarray. During Phase I, Reaction Biology demonstrated that: purified human caspases have robust activities under the reaction conditions of the chip and can be quantitatively measured using the Reaction Biology enzyme chip technology. Through Phase I, RBC has demonstrated feasibility in creating controllable and cost effective caspase chips. Specific Aim 1 involves the validation of caspase assays on microarrays for IC50 profiling and uHTS using a small "standardization" library. Specific Aim 2 involves the screening of two different chemical libraries (totaling 175,000 compounds) against all 10 human caspases. All hits will be verified by measurement of IC50 on the microarrays. Finally, Specific Aim 3 involves the testing of hits in well plate assays against purified caspases and in a cell-based assay of apoptosis. New inhibitors of caspases may lead to advances in the treatment of neurodegenerative processes during acute injury or in chronic disease.